Atrx deficiency induces telomere dysfunction, endocrine defects, and reduced life span
L. Ashley Watson, … , Frank Beier, Nathalie G. Bérubé
L. Ashley Watson, … , Frank Beier, Nathalie G. Bérubé
Published April 8, 2013
Citation Information: J Clin Invest. 2013;123(5):2049-2063. https://doi.org/10.1172/JCI65634.
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Research Article Aging

Atrx deficiency induces telomere dysfunction, endocrine defects, and reduced life span

Abstract

Human ATRX mutations are associated with cognitive deficits, developmental abnormalities, and cancer. We show that the Atrx-null embryonic mouse brain accumulates replicative damage at telomeres and pericentromeric heterochromatin, which is exacerbated by loss of p53 and linked to ATM activation. ATRX-deficient neuroprogenitors exhibited higher incidence of telomere fusions and increased sensitivity to replication stress–inducing drugs. Treatment of Atrx-null neuroprogenitors with the G-quadruplex (G4) ligand telomestatin increased DNA damage, indicating that ATRX likely aids in the replication of telomeric G4-DNA structures. Unexpectedly, mutant mice displayed reduced growth, shortened life span, lordokyphosis, cataracts, heart enlargement, and hypoglycemia, as well as reduction of mineral bone density, trabecular bone content, and subcutaneous fat. We show that a subset of these defects can be attributed to loss of ATRX in the embryonic anterior pituitary that resulted in low circulating levels of thyroxine and IGF-1. Our findings suggest that loss of ATRX increases DNA damage locally in the forebrain and anterior pituitary and causes tissue attrition and other systemic defects similar to those seen in aging.

Authors

L. Ashley Watson, Lauren A. Solomon, Jennifer Ruizhe Li, Yan Jiang, Matthew Edwards, Kazuo Shin-ya, Frank Beier, Nathalie G. Bérubé

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Figure 2

Increased DNA damage and telomere defects in cKO NPCs.

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Increased DNA damage and telomere defects in cKO NPCs. (A) Confocal immu...
(A) Confocal immuno-FISH images of ATRX (red) and telomeres (Tel-FISH; green) in NPCs demonstrates colocalization of the ATRX protein with a subset of telomeres. Scale bar: 5 μm. (B) Confocal immuno-FISH images of γH2AX (red) and telomeres (Tel-FISH; green) shows increased incidence of TIF (γH2AX/Tel-FISH colocalization) in cKO compared with control NPCs (300 nuclei counted, n = 3 control/cKO littermate-matched pairs). Scale bar: 10 μm. (C) DAPI staining of control and cKO metaphase spreads shows representative chromosome fusion in cKO NPC metaphase (arrowhead). Frequency of fusions per metaphase was increased in cKO metaphases compared with control (control: 88 metaphases, cKO: 108 metaphases counted, n = 3). (D) Tel-FISH (green) demonstrates increased telomeric fusions in cKO metaphase chromosomes compared with control (1,475 chromosomes counted; n = 3). (E) Telomere defects (deletion, merge, bridge, and duplication) were scored in control and cKO metaphase chromosomes. Representative images of defects appear to the right of quantification. In all cases, cKO chromosomes showed an increase in telomeric defects compared with control (1,475 chromosomes counted; n = 3). Original magnification, ×1,000 (A and B); ×630 (C–E). *P < 0.05.